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One previously undescribed triterpene glycoside (1) and two known compounds were isolated from the leaves of Cyclocarya paliurus (2-3). Their structures were elucidated based on methods of spectroscopic analysis and NMR data comparison with those in the literature. Compound 1 showed a moderate inhibitory effect on melanogenesis with an IC50 value of 282.3 µM, with the positive drug arbutin showing an IC50 value of 168.5 µM.

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In this study, nine triterpene glycosides including seven previously undescribed compounds (1-7), were isolated from leaves of Cryptolepis buchananii R.Br. ex Roem. and Schult. using various chromatographic methods. The chemical structures of the compounds were elucidated to be 3-O-ß-D-glucopyranosyl-(1 → 6)-ß-D-glucopyranosyluncargenin C 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (1), 3-O-ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyluncargenin C 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (2), 3-O-ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyluncargenin C 28-O-ß-D-glucopyranosyl-(1 → 4)-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (3), 3-O-ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosylhederagenin 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (4), 3-O-ß-D-glucopyranosylarjunolic acid 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (5), 3-O-ß-D-glucopyranosyl-(1 → 2)-ß- D-glucopyranosyl-6ß,23-dihydroxyursolic acid 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (6), 3-O-ß-D-glucopyranosyl-6ß,23-dihydroxyursolic acid 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (7), asiatic acid 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (8), and 3-O-ß-D-glucopyranosylasiatic acid 28-O-α-L-rhamnopyranosyl-(1 → 2)-ß-D-glucopyranosyl ester (9), through infrared, high-resolution electrospray ionization mass spectrometry, one- and two-dimensional nuclear magnetic resonance spectral analyses. The isolates inhibited nitric oxide production in lipopolysaccharide-activated RAW 264.7 cells, with half-maximal inhibitory concentration (IC50) values of 18.8-58.5 µM, compared to the positive control compound, dexamethasone, which exhibited an IC50 of 14.1 µM.

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BACKGROUND: Despite intensive developments of adoptive T cell and NK cell therapies, the efficacy against solid tumors remains elusive. Our study demonstrates that macrophage-based cell therapy could be a potent therapeutic option against solid tumors. METHODS: To this end, we determine the effect of a natural triterpene glycoside, cucumarioside A2-2 (CA2-2), on the polarization of mouse macrophages into the M1 phenotype, and explore the antitumor activity of the polarized macrophage. The polarization of CA2-2-pretreated macrophages was analyzed by flow cytometry and confocal imaging. The anti-cancer activity of CA2-2 macrophages was evaluated against 4T1 breast cancer cells and EAC cells in vitro and syngeneic mouse model in vivo. RESULTS: Incubation of murine macrophages with CA2-2 led to polarization into the M1 phenotype, and the CA2-2-pretreated macrophages could selectively target and kill various types of cancer in vitro. Notably, loading near-infrared (NIR) fluorochrome-labeled nanoparticles, MnMEIO-mPEG-CyTE777, into macrophages substantiated that M1 macrophages can target and penetrate tumor tissues in vivo efficiently. CONCLUSION: In this study, CA2-2-polarized M1 macrophages significantly attenuated tumor growth and prolonged mice survival in the syngeneic mouse models. Therefore, ex vivo CA2-2 activation of mouse macrophages can serve as a useful model for subsequent antitumor cellular immunotherapy developments.

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From the methanol extract of the Cryptolepis buchananii fruits, four undescribed pentacyclic triterpenene glycosides (1-4) and five known pentacyclic triterpenenes (5-9) were isolated. Their structures were determined to be uncargenin C 28-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranosyl ester (1), 3-O-ß-D-glucopyranosyluncargenin C 28-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranosyl ester (2), 3-O-ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl-6ß,23-dihydroxyursolic acid 28-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranosyl ester (3), 3-O-ß-D-glucopyranosyl-(1→2)-ß-D-glucopyranosylasiatic acid 28-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranosyl ester (4), asiatic acid (5), 2α,3ß,23-trihydroxyoleana-11,13(18)-dien-28-oic acid (6), arjunolic acid (7), 6ß-hydroxyarjunolic acid (8), and actinidic acid (9) based on analyses of their HR-ESI-MS, 1D and 2D NMR spectra. All the isolates showed significantly NO production inhibition in LPS-activated RAW264.7 cells with the IC50 values ranging from 18.79 to 37.57 µM, compared to that of the positive control compound, dexamethasone, which showed IC50 value of 14.05 µM.

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Three undescribed triterpene glycosides syzybullosides A-C (1-3) along with fourteen known compounds were isolated from the leaves of Syzygium bullockii (Hance) Merr.& L.M. Perry, including six triterpene glycosides (1-6), four phenolics (7-9, 17), four megastigmanes (10-13), and three flavonoids (14-16). The structures of 1-17 were elucidated by extensive spectroscopic analysis, including IR, HR-ESI-MS, 1D and 2D NMR spectra. Compounds 1-10 and 12-17 inhibited nitric oxide (NO) production in lipopolysaccharide activated RAW264.7 cells with IC50 values ranging from 1.30 to 13.70 µM, lower than that of the positive control compound, L-NMMA (IC50 = 33.8 µM).

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Chemical investigation of the aerial parts of Astragalus lehmannianus Bunge (Leguminosae) led to the isolation and identification of a new cycloartane triterpene glycoside - lehmanniaside (2'-O-acetyl-3-ß-O-D-xylopyranosyl-3ß,6α,16ß,24α-tetrahydroxy-20,25-epoxycycloartane). Its structure was elucidated by means of spectroscopic analysis (HR-MS, 1D and 2D NMR). Bioassays showed that lehmanniaside exhibits weak anthelmintic, antifungal, and cytotoxic activities.

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A new triterpene glycoside, silviridoside, was isolated from the aerial parts of Silene viridiflora (Caryophyllaceae) using different chromatographic techniques. The structure of silviridoside was comprehensively elucidated as 3-O-ß-D-galacturonopyranosyl-quillaic acid 28-O-ß-D-glucopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-ß-D-fucopyranosyl ester by one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). Silviridoside showed promising antioxidant activity in different antioxidant assays such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) (2.32 mg TE/g), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (1.24 mg TE/g), cupric-reducing antioxidant capacity (CUPRAC) (9.59 mg TE/g), ferric-reducing antioxidant power (FRAP) (5.13 mg TE/g), phosphomolybdenum (PHD) (0.28 mmol TE/g), and metal-chelating (MCA) (6.62 mg EDTA/g) assays. It exhibited a good inhibitory potential on acetylcholinesterase (AChE) (2.52 mg GALAE/g), butyrylcholinesterase (BChE) (7.16 mg GALAE/g), α-amylase (0.19 mmol ACAE/g), α-glucosidase (1.21 mmol ACAE/g), and tyrosinase (38.83 mg KAE/g). An in silico evaluation of the pharmacodynamic, pharmacokinetic, and toxicity properties of silviridoside showed that the new compound exhibited reasonable pharmacodynamic and pharmacokinetic properties without any mutagenic effect, but slight toxicity. Thus, it could be concluded that silviridoside could act as a promising lead drug for pharmaceutical and nutraceutical developments to combat oxidative stress and various disorders, but a future optimization is necessary.

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The phytochemical investigations of the seeds of Digitalis purpurea have revealed their richness in cardenolide and pregnane glycosides exhibiting potent cytotoxicity; further chemical examinations of the D. purpurea seeds have achieved the isolation of six triterpene glycosides (1-6), six spirostanol glycosides (7-12), and three furostanol glycosides (13-15), including seven previously unidentified compounds (1-3, 10-12, and 14). Here, the structures of 1-3, 10-12, and 14 were determined via extensive spectroscopic analyses, including two-dimensional (2D) NMR; hydrolysis, followed by chromatographic and spectroscopic analyses; and X-ray crystallographic analysis. The cytotoxic activities of the isolated compounds (1-15) against SBC-3 small cell lung carcinoma and TIG-3 normal human diploid fibroblast cells were evaluated. Triterpene glycoside 3 and spirostanol glycoside 9 exhibited considerable cytotoxicity with IC50 values of 1.0 and 1.7 µM, respectively; they induced apoptotic cell death, which was accompanied by the activation of caspase-3 in SBC-3 cells. Spirostanol glycoside 7 exhibited cytotoxicity toward the SBC-3 cells (IC50 1.3 µM). Additionally, 7 at 0.1 and 1.0 µM synergistically enhanced the cytotoxicity of etoposide against SBC-3 cells; compound 7 induced the release of DAMPs; the release of HMGB1, the secretion of ATP, and the exposure of CALR in the SBC-3 cells. Furthermore, the combination of 7 and etoposide resulted in increasing the extracellular release of DAMPs. These data indicated that 7, as well as its combination with etoposide, might potentially cause immunogenic cell death.

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Two novel triterpene glycosides (1 and 2), 17 known triterpene glycosides (3-19), two known flavonoid glycosides (20 and 21), and two known norsesquiterpene glucosides (22 and 23) were isolated from Hedera rhombea (Araliaceae) leaves. The structures of 1 and 2 were determined by spectroscopic analysis, including two-dimensional NMR spectroscopy, and chromatographic analysis of the hydrolyzed products. The cytotoxicity of the isolated triterpene glycosides (1-19) against HL-60 human promyelocytic leukemia cells was evaluated. Compounds 9, 10, and 11 were cytotoxic to HL-60 cells with IC50 values of 7.2, 21.9, and 32.8 µM, respectively. Other compounds isolated from the leaves were not cytotoxic at sample concentrations of 50 µM.

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Saponaria officinalis L., commonly known as "Soapwort", is a rich source of triterpene glycosides; however, the chemical constituents of S. officinalis seeds have not been fully identified. In this study, we conducted a systematic phytochemical investigation of the seeds of S. officinalis and obtained 17 oleanane-type triterpene glycosides (1-17), including seven new glycosides (1-7). The structures of 1-7 were determined based on a detailed analysis of NMR spectroscopic data and chromatographic and spectroscopic analyses following specific chemical transformation. The cytotoxicities of the isolated compounds were evaluated against HL-60 human promyelocytic leukemia cells, A549 human adenocarcinoma lung cancer cells, and SBC-3 human small-cell lung cancer cells. The cytotoxicities of 1, 4, and 10 toward HL-60 cells and SBC-3 cells were nearly as potent as that of cisplatin. Compound 1, a bisdesmosidic triterpene glycoside obtained in good yield, arrested the cell cycle of SBC-3 cells at the G2/M phase, and induced apoptosis through an intrinsic pathway, accompanied by ROS generation. As a result of the mitochondrial dysfunction induced by 1, mitochondria selective autophagy, termed mitophagy, occurred in SBC-3 cells.

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BC-1 is a cycloartane triterpene glycoside isolated from the whole plant of Beesia calthaefolia. Our recent studies proved that BC-1 inhibited proliferation of splenic lymphocyte and phagocytosis of macrophages, and inhibited the increased production of TNF-α and IL-1ß. However, it lacks of study about the immunomodulatory effect of BC-1 on purified T lymphocytes. Therefore, in the present study, we evaluated the suppressive potentials of BC-1 on immune responses in vitro. BC-1 markedly suppressed anti-CD3/CD28 mAbs (mAbs) induced murine T lymphocytes proliferation, the expression levels of CD69 and CD25 of CD3+ T cells. BC-1 could strongly decrease ratio of CD4+/CD8+, decrease the Th1/Th2 cytokines production (IL-2, IFN-γ, IL-4, and IL-10) of CD4+ T-cells. In addition, we studied signal transduction pathways about T-cell activation on puried murine CD4+ T lymphocytes by western-blot assay. The data revealed that BC-1 could inhibit the activation of JNK, ERK and PI3K/AKT signal transduction pathways. These results indicated that BC-1 possesses potential downregulating effect on the immune system and might be developed as an immunosuppressive agent in treatment of CD4+ T cell-mediated inflammatory and undesired immune responses.

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Our continuing search for marine bioactive secondary metabolites led to the screening of crude extracts of sea cucumbers by the model of Pyricularia oryzae. A new sulfated triterpene glycoside, coloquadranoside A (1), together with four known triterpene glycosides, philinopside A, B, E and pentactaside B (2-5) were isolated from the sea cucumber Colochirus quadrangularis, and their structures were elucidated using extensive spectroscope analysis (ESI-MS, 1D and 2D NMR) and chemical methods. Coloquadranoside A possesses a 16-acetyloxy group in the holostane-type triterpene aglycone with a 7(8)-double bond, a double bond (25,26) at its side chain, and two ß-d-xylose in the carbohydrate chain. Coloquadranoside A exhibits in vitro some antifungus, considerable cytotoxicity (IC50 of 0.46-2.03 µM) against eight human tumor cell lines, in vivo antitumor, and immunomodulatory activity.

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This research isolated two new oleanane-type triterpene glycosides, named mocochinosides A (1) and B (2), together with ten known compounds as chikusetsusaponin IVa ethyl ester (3), momordin Ib (4), momordin IIb (5), momordin II (6), calenduloside G (7), calenduloside H (8), elatoside A (9), elatoside C (10), calendulaglycoside C 6'-O-7-butyl ester (11), and hederagenin 3-O-ß-D-glucuronopyranoside (12) and characterized them from the vines of Momordica cochinchinensis. The new structures of both glycosides 1-2 were elucidated by spectroscopic analysis including 2 D NMR and MS, followed by an analysis of their anti-inflammatory and cytotoxic activities. Compounds 1, 4, and 11 showed moderate inhibitions for NO production on RAW264.7 macrophages induced by LPS at IC50 5.41 ∼ 11.28 µM. Compounds 3, 4, and 7 (IC50 8.42 ∼ 19.74 µM) exhibited potential anti-proliferative activities against both of WiDr and MCF-7 human tumor cell lines.

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Transient receptor potential ankyrin 1 (TRPA1) is a cation channel that plays a critical role in the occurrence and transmission of pain. By screening 393 marine invertebrate extracts for their antagonistic activity against TRPA1, it was found that the extract of the edible sea cucumber Bohadschia vitiensis had a remarkable potency. Bioassay-guided separation of the extract resulted in the isolation of six triterpene glycosides, including a novel analog. All six isolated compounds exhibited high inhibitory potency against TRPA1 (IC50 values ranging from 0.60 to 3.26 µM), which is comparable to that of a previously developed synthetic antagonist (A-967079). The discovery of TRPA1 antagonists, originated from this edible sea cucumber, opens the door for the elaboration of the valuable triterpene scaffold for the development of novel safe analgesics.

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One new triterpene glycoside, asiaticoside I (1), along with seven known ones (2-8), were isolated from the aerial parts of Cimicifuga dahurica (Turcz.) Maxim. The structure of 1 was elucidated on the basis of extensive spectroscopic methods including 1D-NMR, 2D-NMR and MS data. The structures of known compounds were determined by comparison with the literature data. Compound 1 exhibited moderate cell growth inhibitory activities in vitro against HELF, non-small cell lung cancer A549, and pancreatic cancer PANC-1 cell lines, with IC50 values of 62.97, 43.19, and 60.40 µM, respectively.

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From the MeOH extract of the Vietnamese sea cucumber Holothuria edulis, eight triterpene glycosides (1-8), including one new compound namely holothurin A5 (1), were isolated by using various chromatographic separations. Their structures were established by spectroscopic experiments including 1D, 2D NMR and HR-ESI-MS. Holothurin A5 (1) has a hydroperoxy group at C-25. To the best of our knowledge, this is the first report of this group in triterpene saponins obtained from sea cucumbers to date. In addition, the in vitro cytotoxicity against five human cancer cell lines (HepG2, KB, LNCaP, MCF7 and SK-Mel2) of all isolated compounds was also evaluated using SRB assays.

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One triterpene and five triterpene glycosides, including four new compounds, have been identified in the underground parts of Glycyrrhiza bucharica, which was shown to be closely related to Glycyrrhizin-producing Glycyrrhiza species, G. uralensis, G. glabra and G. inflata, based on their chloroplast rbcL sequences. Two known compounds were identified squasapogenol and macedonoside C. The structures of four new compounds, bucharosides A, B, C, and D, were determined to be 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucuronopyranosyl-(1→2)-ß-D-glucuronopyranosyl-22-O-α-L-rhamnopyranosyl squasapogenol, 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucuronopyranosyl-(1→2)-ß-D-glucuronopyranosyl-macedonic acid, 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucuronopyranosyl-(1→2)-ß-D-glucuronopyranosyl-squasapogenol, and 22-O-α-L-rhamnopyranosyl squasapogenol, respectively. Contents of these triterpene glycosides were less than 0.5% of dry weight, and no main saponin, like glycyrrhizin or macedonoside C found in other Glycyrrhiza species, was found in the underground parts of G. bucharica.

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Two new triterpene glycosides (1 and 2), together with nine known triterpene glycosides (3-11), were isolated from the seeds of Dolichos lablab (Leguminosae). The structures of the new compounds were determined by spectroscopic analysis, including two-dimensional NMR spectroscopy, and chromatographic analysis of the hydrolyzed products. The isolated compounds did not show cytotoxicity against HL-60 human leukemia cells and HepG2 human hepatoma cells at sample concentrations of 20 µM.

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Previous studies indicate that the herb black cohosh (Actaea racemosa L.) and the triterpene glycoside actein inhibit the growth of human breast cancer cells and activate stress-associated responses. This study assessed the transcriptomic effects of black cohosh and actein on rat liver tissue, using Ingenuity and ToxFX analyses. Sprague-Dawley rats were treated with an extract of black cohosh enriched in triterpene glycosides (27%) for 24 h or actein for 6 and 24 h, at 35.7 mg/kg, and liver tissue collected for gene expression analysis. Ingenuity analysis indicates the top canonical pathways are, for black cohosh, RAR Activation, and, for actein, Superpathway of Cholesterol Biosynthesis, at 24 h. Actein alters the expression of cholesterol biosynthetic genes, but does not inhibit HMG-CoA reductase activity. Black cohosh and actein inhibited the growth of human breast and colon cancer cells and synergized with the statin simvastatin. Combinations of black cohosh with certain classes of statins could enhance their activity, as well as toxic, such as inflammatory liver, side effects. Transcriptomic analysis indicates black cohosh and actein warrant further study to prevent and treat cancer and lipid disorders. This study lays the basis for an approach to characterize the mode of action and toxicity of herbal medicines.

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Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A1 is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C2, the 25(26)-dihydro derivative of holotoxin A1 induced apoptosis in human leukemia cells by activating ceramide synthase 6. Thus, we hypothesized that holotoxin A1, which is structurally similar to cladoloside C2, might induce apoptosis in human leukemia cells through the same molecular mechanism. In this paper, we compared holotoxin A1 and cladoloside C2 for killing potency and mechanism of action. We found that holotoxin A1 induced apoptosis more potently than cladoloside C2. Moreover, holotoxin A1-induced apoptosis in K562 cells by activating caspase-8 and caspase-3, but not by activating caspase-9. During holotoxin A1-induced apoptosis, acid sphingomyelinase (SMase) and neutral SMase were activated in both K562 cells and human primary leukemia cells. Specifically inhibiting acid SMase and neutral SMаse with chemical inhibitors or siRNAs significantly inhibited holotoxin A1-induced apoptosis. These results indicated that holotoxin A1 might induce apoptosis by activating acid SMase and neutral SMase. In conclusion, holotoxin A1 represents a potential anticancer agent for treating leukemia. Moreover, the aglycone structure of marine triterpene glycosides might affect the mechanism involved in inducing apoptosis.

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